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Discovery of Potent and Selective MTH1 Inhibitors for Oncology: Enabling Rapid Target (In)Validation
journal contribution
posted on 2019-11-18, 22:18 authored by Julie Farand, Jeffrey E. Kropf, Peter Blomgren, Jianjun Xu, Aaron C. Schmitt, Zachary E. Newby, Ting Wang, Eisuke Murakami, Ona Barauskas, Jawahar Sudhamsu, Joy Y. Feng, Anita Niedziela-Majka, Brian E. Schultz, Karen Schwartz, Serge Viatchenko-Karpinski, Dmytro Kornyeyev, Adam Kashishian, Peidong Fan, Xiaowu Chen, Eric B. Lansdon, Michael O. Ports, Kevin S. Currie, William J. Watkins, Gregory T. NotteWe describe the discovery of three structurally differentiated
potent and selective MTH1 inhibitors and their subsequent use to investigate
MTH1 as an oncology target, culminating in target (in)validation.
Tetrahydronaphthyridine 5 was rapidly identified as a
highly potent MTH1 inhibitor (IC50 = 0.043 nM). Cocrystallization
of 5 with MTH1 revealed the ligand in a Φ-cis-N-(pyridin-2-yl)acetamide conformation
enabling a key intramolecular hydrogen bond and polar interactions
with residues Gly34 and Asp120. Modification of literature compound TH287 with O- and N-linked
aryl and alkyl aryl substituents led to the discovery of potent pyrimidine-2,4,6-triamine 25 (IC50 = 0.49 nM). Triazolopyridine 32 emerged as a highly selective lead compound with a suitable in vitro profile and desirable pharmacokinetic properties
in rat. Elucidation of the DNA damage response, cell viability, and
intracellular concentrations of oxo-NTPs (oxidized nucleoside triphosphates)
as a function of MTH1 knockdown and/or small molecule inhibition was
studied. Based on our findings, we were unable to provide evidence
to further pursue MTH1 as an oncology target.